Project Summary The National Comprehensive Cancer Network (NCCN) defines CRF as ?a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning?. CRF, which affects from 60- 100% of patients on active cancer treatment, is usually greatest immediately following treatment, returning to baseline before the next treatment, but increasing in severity and duration with successive rounds of treatment. Approximately 30% of breast cancer survivors (BCS) continue to experience moderate to severe fatigue, which may last as long as 10 years after treatment. CRF has a major impact on quality of life both and physical functioning. Reduced physical fitness as a result of cardiorespiratory and skeletal muscle deconditioning, as well as neuromuscular dysfunction has been proposed to contribute to the subjective sensation of CRF in BCS. Collectively these factors impact fatigability, which herein, we define as a loss of muscle force and power, decreased endurance, and an increase in perceived effort during muscular exercise. In non-cancer populations, increased fatigability particularly of the lower extremities is associated with functional impairments like postural instability, reduced gait speed, and increased risk of falls. There have not been any studies to date that have examined the relationship between self-reported CRF and fatigability, or CRF and fatigue recovery using a muscle fatiguing protocol that targets the lower extremities. Indeed, studies to date that did examine lower extremity muscle strength in cancer survivors under non-fatiguing conditions or if fatiguing conditions were used it is usually focused on isolated muscle groups. Importantly, no studies have sought to examine the association between fatigability on functional parameters like postural stability, and gait speed in cancer survivors with and without CRF. To address these gaps in the literature we propose to examine the impact of lower extremity muscle fatigue on lower extremity muscle force and power, postural stability and gait speed over time in persistently fatigued and non-fatigued breast cancer survivors matched on age and cancer stage. We hypothesize that BCS with CRF will show increased fatigability, diminished recovery from fatiguing exercise, and consequently greater post-exertional impairments in function (reduced postural stability and gait speed) following fatiguing exercise that targets the lower extremities than their non-fatigued counterparts. In this two year pilot study we propose to address the following aims: 1) Determine whether BCS with CRF have increased fatigability compared to non-fatigued BCS, 2) Determine whether BCS with CRF have slower recovery from fatigue compared to non-fatigued BCS , 3) Determine whether BCS with CRF have greater functional impairments following lower extremity muscle fatiguing exercise compared to BCS without CRF, and 4) (Exploratory) Determine whether increased fatigability mediates the relationship between fatigue group (CRF vs non-Non-CRF) and functional outcomes (change in sway velocity, and gait speed).